Adv Physiol Educ 33: 165–168, 2009;
doi:10.1152/advan.00023.2009.
Using Classic Papers To Teach Physiology
Teaching the role of secretin in the regulation of gastric acid secretion using a
classic paper by Johnson and Grossman
Kristen L. W. Walton
Department of Biology, Missouri Western State University, St. Joseph, Missouri
Submitted 31 March 2009; accepted in final form 14 May 2009
gastrin; gastrointestinal tract; education
FOR OVER 100 YEARS,
scientists have investigated the process of
digestion and the production of gastric acid. Decades of research support a model of gastric acid secretion that includes
three phases: 1) the cephalic phase, in which visual, olfactory,
or taste stimuli as well as the very thought of food, trigger
gastric acid secretion via parasympathetic activity through the
vagus nerve; 2) the gastric phase, in which local enteric as well
as vagal reflexes combine with the production of the hormone
gastrin to stimulate gastric acid secretion; and 3) the intestinal
phase, which is characterized by the production of lower levels
of gastric acid. Gastrin acts via the direct stimulation of acid
secretion by parietal cells as well as by the stimulation of
histamine release by enterochromaffin-like cells (ECL), which
provides an additional stimulus of parietal cell activity. As
chyme enters the small intestine, gastric acid secretion is
inhibited in a negative feedback loop, which is mediated by
both nervous reflexes and hormonal controls. Secretin is a
hormone produced by S cells in the mucosa of the duodenum
and jejunum that plays a major role in neutralizing the acidity
of the duodenum. Secretin is primarily associated with promoting the secretion of bicarbonate ions by the exocrine pancreas,
but an additional important effect of secretin is to inhibit
gastric acid secretion by inhibiting the secretion of gastrin.
Address for reprint requests and other correspondence: K. L.W. Walton,
Dept. of Biology, Missouri Western State Univ., 4525 Downs Dr., St. Joseph,
MO 64507 (e-mail: [email protected]).
These actions of secretin combine to result in the neutralization
of the acidic duodenal contents.
Research on the Regulation of Gastric Acid Secretion
Ivan P. Pavlov, the winner of a Nobel Prize for Physiology
or Medicine in 1904, was the first to demonstrate that gastric
acid secretion was stimulated by the anticipation of a meal,
using a surgical procedure in dogs called the Pavlov pouch (for
review, see Ref. 10). This preparation involved surgically
creating a pouch from the main stomach with a cannula that
allowed direct sampling of gastric secretions. The Pavlov
pouch was similar to a surgical preparation called a Heidenhain
pouch after its inventor, Dr. Rudolf Heidenhain; the primary
difference between the Pavlov pouch and the Heidenhain
pouch was the maintenance of intact vagal innervation in the
former and the lack of vagal innnervation in the latter (for
reviews, see Refs. 10 and 11). These innovative surgical
preparations were used as an experimental model for decades,
providing gastrointestinal physiologists with the ability to
directly measure gastric acid secretion in live, nonanesthetized
dogs.
Dr. Morton Grossman was a prolific, highly respected researcher who published many seminal papers in gastrointestinal physiology; a tribute to Dr. Grossman’s work was recently
published by Guth and Kaunitz (7). Dr. Leonard Johnson
worked as a postdoctoral fellow with Dr. Grossman, and he
continues to publish highly regarded work in gastrointestinal
physiology. These two physiologists, both leaders in the field,
published together several important and elegant studies to
elucidate the mechanisms involved in the regulation of gastric
and pancreatic secretions. Their classic paper, titled “Secretin:
the enterogastrone released by acid in the duodenum,” represents in a few clear figures the culmination of much work to
identify secretin as the agent secreted by the intestinal mucosa
that inhibited gastrin-induced gastric acid secretion (9).
Secretin was first identified by Bayliss and Starling in 1902,
when they observed that the infusion of acid into a denervated
loop of the jejunum resulted in the stimulation of pancreatic
secretions (2). They were the first to use the term “hormone” to
describe the active chemical agent secreted by the intestinal
mucosa. Later researchers determined that a substance released
into the blood from the intestinal mucosa, upon contact with
acid, inhibited gastric acid secretion (1). The term “enterogastrone” was used to describe intestine-derived inhibitors of
gastric secretions (6), and secretin was considered a likely
candidate. A series of experiments published by Morton Grossman and others determined that the intravenous injection of
secretin purified from extracts of the duodenal mucosa inhibited gastrin-induced acid secretion in Heidenhain pouches (4,
5, 12). However, it remained to be demonstrated that exogenous secretin could account for the same level of inhibition of
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Walton KL. Teaching the role of secretin in the regulation of gastric acid
secretion using a classic paper by Johnson and Grossman. Adv Physiol Educ
33: 165–168, 2009; doi:10.1152/advan.00023.2009.—The regulation of
gastric acid secretion has been the subject of investigation for over a
century. Inhibition of gastrin-induced acid secretion by the intestinederived hormone secretin provides a classic physiological example of
negative feedback in the gastrointestinal tract. A classic paper by
Leonard R. Johnson and Morton I. Grossman clearly shows the ability
of secretin to negatively regulate gastric acid secretion, providing
students with an example of this feedback loop. In addition, this
article demonstrates the step forward in gastrointestinal endocrinology
that occurred when pure preparations of secretin and other gastrointestinal hormones first became available. The comparison of the
effects of exogenous, purified secretin to the physiological stimulus of
acid in the duodenum is an important example of how newly available
reagents allow scientists such as Johnson and Grossman to clarify the
mechanisms behind previously established processes. One or more
figures from this classic paper can be used to give students insight into
the role of secretin in the regulation of the function of the gastrointestinal tract and will also give students a clear example of how the
careful experimentation and clear interest in gastrointestinal physiology led Johnson and Grossman to advance the field.
Using Classic Papers To Teach Physiology
166
TEACHING WITH A CLASSIC PAPER BY JOHNSON AND GROSSMAN
Figures for Discovery Learning
Figure 1 from this article can be used to illustrate for
students the Heidenhain pouch surgical procedure that allowed
Johnson and Grossman to both measure gastric acid secretion
and infuse saline or acid into the duodenum in dogs. This
preparation is a classical experimental model that allowed the
in vivo detection of the physiological control of the gastric acid
secretory response. An important point is that the Heidenhain
Fig. 1. Original Fig. 1 from Johnson and Grossman. This diagram shows the
Heidenhain pouch preparation used for the experiments reported in this article.
Secretions from the Heidenhain pouch were collected through the Gregory
cannula and measured to quantify gastric acid secretion. Saline or HCl was
instilled into the duodenum via the Gregory cannula. An intravenous catheter
was also created to allow the intravenous infusion of secretin.
pouch, in contrast to the Pavlov pouch, does not preserve the
vagal innervation to the stomach pouch; this allows the effects
of hormones to be studied in isolation of nervous reflexes to the
tissue.
Figure 2 of this article illustrates the major finding of the
classic paper: that the infusion of secretin caused a nearcomplete inhibition of gastric acid secretion that was similar in
magnitude and kinetics to the inhibition produced by instillation of acid into the duodenum. Basal secretions were collected
at the beginning of each experiment. After 1 h of basal
conditions, purified gastrin was infused intravenously, and an
increased production of acid was rapidly observed (as shown
by an increase in H⫹ concentration). In control experiments,
saline was continuously infused into the duodenum, and the
acidity of secretions in the Heidenhain pouch was maintained at a relatively constant pH. However, when pure
secretin was administered intravenously over a 1-h period,
gastrin-induced acid secretion was rapidly and dramatically
reduced. In an important physiological comparison experiment,
the infusion of acid at a physiological concentration through
the duodenal cannula also resulted in a rapid inhibition of
acidity of the Heidenhain pouch secretions, although the magnitude and duration of the maximal response to acid was
slightly less than the response to exogenous secretin. This dose
of gastrin had previously been demonstrated to be submaximal;
the authors also show data from a similar series of experiments
using near-maximal doses of gastrin stimulation (Fig. 3 in the
original paper, not shown). Similar results were seen in these
experimental conditions, further supporting the hypothesis that
secretin was the primary mediator of the effects of intestinal
acidification on gastrin-induced gastric acid secretion.
The final figure in the current article is Fig. 3 (Fig. 4 in the
original paper). This series of experiments was similar to those
shown in Fig. 2 but used histamine rather than gastrin to
stimulate gastric acid secretion. Consistent with prior work (4,
5), histamine caused an increase in gastric acid production, but
neither acid in the duodenum nor intravenous secretin altered
histamine-induced acid secretion. This serves as an additional
demonstration that exogenous purified secretin had effects
consistent with the physiological effects of acid in the duodenum. Later studies have reported that secretin decreases gastrin
release (8), with effects on gastrin and gastric acid output
mediated at least in part by the stimulation of somatostatin and
prostaglandin release (3, 8).
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gastrin-induced gastric acid secretion as the presence of acid in
the duodenum. This paper by Johnson and Grossman (9)
compared the effects of a 1-h continuous intravenous infusion
of secretin to the effects of an infusion of HCl into the
duodenum on gastric secretions to determine whether secretin
could indeed account for the same level of inhibition as acid in
the duodenum. The ability of exogenous hormone to recapitulate physiological effects is an important criterion in determining whether that hormone has physiological action.
As these experiments were done well before recombinant
technology allowed the large-scale production of recombinant
hormones, physiologists at this time relied on purified hormone
extracts made from tissues and glands or on newly available
synthetic hormones. This paper by Johnson and Grossman used
commercially available pure secretin given by a 1-h continuous
intravenous infusion, which approximated the physiological
production of secretin in response to acidification of the intestinal contents. This classic paper is useful for reinforcing the
concept of hormonal control of gastric acid secretion. It is also
an excellent demonstration for students of how gastrointestinal
physiologists determined whether specific hormones were involved in physiological responses. Students should have some
introductory background in gastrointestinal physiology and
gastric acid production before this activity, either through
assigned reading or through previous lectures and discussions.
For a short in-class or out of class activity appropriate for
undergraduates, Fig. 2 from this article and the associated
questions can be distributed to your students. For a 30- to
45-min in-class activity, the instructor may wish to introduce
the historical context, general background, and experimental
design for Fig. 2 with a brief (10 min) lecture. Students can
then work in groups of two to four students to answer the
discovery learning questions for an additional 10 –20 min. The
groups can then reconvene for a 10- to 15-min class discussion
of the data and questions.
For a longer, more in-depth study for undergraduates or
beginning graduate students, the entire paper can be assigned
together with the associated questions. In this model, I suggest
providing the full paper and questions to students to be read
and completed outside of class. The questions can be turned in
as an independent assignment; alternatively, students can work
in groups for 10 –20 min to discuss their prepared answers at
the beginning of the next class session. This can be followed by
handing in the assignment or by class discussion of the data
and questions, depending on the instructor’s preferences and
the amount of time available. I have successfully used Fig. 2
and the associated questions as an out of class, independent
assignment in a one-semester anatomy and physiology course
for prenursing students with relatively little previous background in reading primary literature, and I believe that the full
paper could readily be adapted for use in different courses
depending on students’ backgrounds.
Using Classic Papers To Teach Physiology
TEACHING WITH A CLASSIC PAPER BY JOHNSON AND GROSSMAN
Student Learning Outcomes
Questions 7–9 can be included if the entire paper is assigned.
Question 7. Briefly describe the effects of each of the following on gastric acid secretion based on the data shown in
Fig. 3 (Fig. 4 in the original paper):
A. Intravenous infusion of histamine.
B. Intravenous administration of secretin in the presence of
intravenous histamine.
C. Addition of acid to the duodenum in the presence of
intravenous histamine.
Question 8. Based on the data presented in the paper as a
whole, predict a mechanism through which secretin may regulate gastric acid secretion.
Question 9. Techniques available for the investigation of
hormonal control of gastric acid secretion and other physiological parameters have advanced significantly in the 40 years
since this study was published. Design an experiment using
modern techniques to further investigate the role of secretin in
the regulation of gastric acid secretion. Suggested techniques
include (but are not limited to) the use of transgenic and/or
knockout animal models, analysis of RNA or protein localization or expression levels, and the use of receptor agonists and
antagonists or blocking antibodies.
Teaching Points
After completing this activity, students will be able to:
1. Explain the role of secretin and other factors in the
regulation of gastric acid secretion and in the process of
digestion.
2. Critically analyze experimental data in gastrointestinal
physiology.
3. Discuss appropriate experimental design to investigate the
effects of hormones on gastric acid secretion.
Questions for Discovery Learning
Question 1. Describe the cephalic, gastric, and intestinal
phases of gastric secretion.
Question 2. Figure 1 shows the Heidenhain pouch model
system used in this paper. A similar model system called the
Pavlov pouch differs in that the Pavlov pouch model retains
innervation by the vagus, but the Heidenhain pouch does not.
Propose an experimental question about gastric acid secretion
that would be best addressed using 1) a Pavlov pouch and 2) a
Heidenhain pouch.
Question 3. What physiological event is mimicked by the
infusion of acid (HCl) into the duodenum, as represented by
the “HCl” line in the graph shown in Fig. 2? What is the
purpose of including this experimental group?
Question 4. Briefly describe the effects of each of the following on gastric acid based on the data shown in Fig. 2:
A. Intravenous administration of gastrin.
B. Intravenous administration of secretin in the presence of
intravenous gastrin.
C. Addition of acid to the duodenum in the presence of
intravenous gastrin.
Question 5. How does the effect of secretin compare with
the effect of acid in the duodenum? Does this support the
conclusion that the effects of acid in the duodenum on gastric
acid secretion are mediated primarily by secretin?
Question 6. Explain the other effects of secretin on the
gastrointestinal tract and how the effects of secretin combine to
regulate digestion.
Teaching point 1. Both nervous reflexes and hormonal
controls contribute to the regulation of gastric acid secretion.
The relative importance of vagus input versus hormonal and
chemical messengers was the subject of debate for decades,
beginning with Pavlov. The use of the Heidenhain pouch
(shown in Fig. 1), in which the vagus innervation is not
preserved, allowed researchers to investigate gastric acid regulation in the absence of higher nervous system regulation.
Although this does not allow direct study of the interplay
between neural and hormonal controls, it provides an experimental model that allowed researchers to determine that hormones were important players in gastrointestinal physiology.
Teaching point 2. The inclusion of appropriate controls is
vital to clearly demonstrating whether exogenous hormones
can recapitulate physiological responses. The negative control
in these experiments was the infusion of saline into the duo-
Fig. 3. Original Fig. 4 from Johnson and Grossman. The experimental setup is
the same as in Fig. 2 except that the stimulation of gastric acid secretion was
by an infusion of histamine rather than gastrin.
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Fig. 2. Original Fig. 2 from Johnson and Grossman. The acidity of secretions
collected from the Heidenhain pouch is shown. All dogs received an intravenous infusion of gastrin for the indicated time period. Control data represent
dogs that received saline in the duodenal cannula. HCl data represent dogs that
received an infusion of HCl in the duodenal cannula for the indicated time
period, and the secretin data points were collected while dogs received an
intravenous infusion of purified secretin for the indicated time period.
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TEACHING WITH A CLASSIC PAPER BY JOHNSON AND GROSSMAN
Conclusions
This classic paper by Johnson and Grossman provides a
clear picture of the role of gastrin and secretin in the regulation
of gastric acid secretion and also gives students an opportunity
to engage in the process of science and careful experimentation. The experiments presented do not require students to have
an extensive understanding of experimental techniques, as the
readout for all the data figures is simply acid production by a
surgically created pouch of the stomach. The regulation of
gastric acid secretion by parietal cells is complex and involves
an interplay between multiple factors, including gastrin, histamine, and acetylcholine. More recent journal articles or textbook readings will allow a more in-depth discussion of the
cellular mechanism of gastric acid secretion as a followup to
this activity, if desired. However, this paper from 1968, which
includes in its references articles from the 1920s, will give
student a glimpse of the experiments over the past century that
have led to our current understanding of the physiology of
gastric secretion.
REFERENCES
1. Andersson S. Inhibitory effects of acid in antrum-duodenum on fasting
gastric secretion in Pavlov and Heidenhain pouch dogs. Acta Physiol
Scand 49: 42–56, 1960.
2. Bayliss WM, Starling EH. The mechanism of pancreatic secretion.
J Physiol 28: 325–353, 1902.
3. Chung I, Li P, Lee K, Chang T, Chey WY. Dual inhibitory mechanism
of secretin action on acid secretion in totally isolated, vascularly perfused
rat stomach. Gastroenterology 107: 1751–1758, 1994.
4. Gillespie IE, Grossman MI. Inhibitory effect of secretin and cholecystokinin on Heidenhain pouch responses to gastrin extract and histamine.
Gut 5: 342–345, 1964.
5. Greenlee HB, Longhi EH, Guerrero JD, Nelsen TS, El-Bedri AL,
Dragstedt LR. Inhibitory effect of pancreatic secretin on gastric secretion.
Am J Physiol 190: 396 – 402, 1957.
6. Gregory RA. Enterogastrone–a reappraisal of the problem. In: Gastric
Secretion, edited by Shnitka TK, Gilbert JAL, Harrison RC. New York:
Pergamon, 1967, p. 477– 499.
7. Guth PH, Kaunitz JD. Personal reminiscences about Morton Grossman
and the founding of the Center for Ulcer Research and Education (CURE).
Am J Physiol Gastrointest Liver Physiol 294: G1109 –G1113, 2008.
8. Jin HO, Lee KY, Chang TM, Chey WY, Dubois A. Secretin: a
physiological regulator of gastric emptying and acid output in dogs. Am J
Physiol Gastrointest Liver Physiol 267: G702–G708, 1994.
9. Johnson LR, Grossman MI. Secretin: the enterogastrone released by acid
in the duodenum. Am J Physiol 215: 885– 888, 1968.
10. Smith GP. Pavlov and integrative physiology. Am J Physiol Regul Integr
Comp Physiol 279: R743–R755, 2000.
11. Wood JD. The first nobel prize for integrated systems physiology: Ivan
Petrovich Pavlov, 1904. Physiology (Bethesda) 19: 326 –330, 2004.
12. Wormsley KG, Grossman MI. Inhibition of gastric acid secretion by
secretin and by endogenous acid in the duodenum. Gastroenterology 47:
72– 81, 1964.
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denum of gastrin-stimulated dogs. Gastrin (or histamine) was
able to induce marked secretion of gastric acid (HCl) (Figs. 2
and 3). The infusion of acid into the duodenum is a critical
physiological control, as it represents the transit of acidic
chyme from the stomach to the duodenum. The ability of
exogenous secretin to have as strong an effect as the physiological stimulus of acid in the duodenum is a crucial piece of
evidence supporting the physiological role of secretin in the
regulation of gastric acid secretion.
Teaching point 3. In addition, the demonstration that acidification of the intestinal luminal contents triggers mechanisms
that decrease gastric acid output provides a good example of
negative feedback loops in the gastrointestinal tract. As acidified chyme moves from the stomach into the duodenum, the
intestine signals back to the stomach to decrease the production
of acid and slow the digestive process. This allows time for
further digestion to occur in the intestine, as well as absorption
of nutrients, before a new bolus of chyme enters from the
stomach.
Teaching point 4. Secretin was first identified as and is still
primarily considered to be an intestine-derived stimulator of
pancreatic secretion. This stimulation of bicarbonate ion secretion from the pancreas has the functional consequence of
neutralizing the pH of the intestinal contents. Although it can
be challenging for beginning students of endocrinology and
physiology to appreciate that hormones can stimulate one
effector yet inhibit another, the concomitant stimulation of
pancreatic secretions and inhibition of gastric acid production
both act to bring the pH of the duodenal contents to a more
neutral value.